Innate immunity to virus infection

Abstract

The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Three classes of receptors, designated retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs), sense viral components, such as double-stranded RNA (dsRNA), single-stranded RNA, and DNA. RLRs and TLRs play essential roles in the production of type I interferons (IFNs) and proinflammatory cytokines in cell type-specific manners. While the RLRs play essential roles in the recognition of RNA viruses in various cells, plasmacytoid dendritic cells utilize TLRs for detecting virus invasion. NLRs play a role in the production of mature interleukin-1 beta to dsRNA stimulation. Activation of innate immune cells is critical for mounting adaptive immune responses. In this review, we discuss recent advances in our understanding of the mechanisms of viral RNA recognition by these different types of receptors and its relation to acquired immune responses.

Figure 1

Differential roles of RIG-I and MDA5 in RNA virus recognition. RIG-I recognizes 5′-triphosphate RNA and short dsRNA, whereas MDA5 discriminates long dsRNA generated during the course of virus infection. RNA viruses are differentially recognized by RIG-I and MDA5. RIG-I is responsible for detecting Paramyxoviridae, Orthomyxoviridae, Rhabdoviridae and some Flaviviridae family members. On the other hand, MDA5 recognizes Picornaviridae family members. Some viruses such as West Nile virus and Reovirus are detected by both RIG-I and MDA5. LGP2 is reported to be a genitive regulator for the RIG-I and MDA5 signaling.

Figure 2

Three classes of PRRs for RNA virus recognition. ssRNA from viruses is recognized by TLR7 in pDCs, whereas dsRNA is detected by TLR3 in cDCs. TLR7 and TLR3 trigger signaling cascades via the adaptors MyD88 and TRIF, respectively. RIG-I and MDA5 recruit another adaptor protein, IPS-1. TRIF and IPS-1 share signaling molecules for phosphorylation of IRF-3 and IRF-7 by TBK1/IKK/i. MyD88-dependent signaling directly activates IRF-7 in pDCs. Phosphorylated IRF-3 and IRF-7 activate the expression of type I IFN genes. Simultaneously, TLRs and RLRs induce the translocation of NF-κB to induce the expression of cytokine genes via distinct adaptor proteins. On the other hand, one of the NLR proteins, NALP3, detects the presence of dsRNA and induces the catalytic activity of caspase-1 via an adaptor, ASC. Caspase-1 is essential for cleavage of pro-IL-1β to the mature form.